Carbonyldiimidazoles, their ester derivatives and method for their production

ABSTRACT

Carbonyldiimidazoles of the formulae Ia, Ib, Ic or mixtures thereofwhere R1 is C1-4-alkyl and R2 is hydrogen or methyl, and tert-butyl esters derived therefrom are described.

The invention relates to certain carbonyldiimidazoles, esters derivedtherefrom, processes for their preparation and their use.

In the synthesis of peptides from amino acids, protection of thefunctional groups not involved in the reaction is absolutely necessaryin order to obtain a homogeneous product. One of the most importantprotective groups, which is also used industrially, for the amino groupof amino acids is the tert-butyloxycarbonyl group, which is usuallyabbreviated to BOC. In this case, the amino functionality is protectedas urethane, and the protective group can be eliminated again under mildacidic conditions.

Urethanes are normally prepared by reacting amino groups with achloroformate. However, tert-butyl chloroformate is extremely unstableand thus can be handled only with difficulty. It is therefore unsuitablefor introducing the BOC protective group. Numerous compounds intended tobe used to protect amino groups with BOC are described in theliterature.

The compound used most often for introducing BOC protective groups isdi-tert-butyl dicarbonate, also referred to as di-tert-butylpyrocarbonate or BOC anhydride ((CH₃)₃C—O—CO—O—CO—O—C(CH₃)₃).Processesfor preparing BOC anhydride are disclosed,for example, in U.S. Pat. Nos.5,162,565 and 5,162,565 and EP-A-0 468 404. The processes for preparingBOC anhydride are multistage and include elaborate steps using costlychemicals. This is why BOC anhydride is very costly and is reluctantlyemployed as compound in industrial reactions.

One example of other compounds for introducing the BOC protective groupis BOC fluoride as described in Liebigs Ann. Chem. 716 (1968) 175-185.

J. Org. Chem. 50 (1985) 3951-3953 describes the preparation of1,2,2,2-tetrachloroethyl tert-butyl carbonate and its use forintroducing BOC protective groups.

Helv. Chim. Acta 44 (1961), 2151, Spec. Chem. 13 (1993), 67-69 andEP-A-0 236 888 describe the preparation oftert-butyloxycarbonylimidazole from carbonyldiimidazole and its use forintroducing the BOC protective group.

Whereas BOC fluoride can be synthesized only via carbonyl fluoridechloride, which is elaborate to prepare, and therefore has only minorimportance, the two other compounds are solids which require elaboratetechniques for isolation and purification. Other BOC-introducingreagents have no industrial importance because of their instability.

It is an object of the present invention to provide compounds forintroducing BOC protective groups which can be obtained via lesselaborate steps from compounds which are easy to obtain. The compoundsshould furthermore be liquid at room temperature and be amenable todistillation without decomposition under reduced pressure. They shouldfurthermore have a long shelf life and avoid the disadvantages of knowncompounds.

We have found that this object is achieved by imidazolecarboxylic estersof the formulae IIIa and IIIb or mixtures thereof

where R¹ is C₁₋₄-alkyl and R² is hydrogen or methyl.

The imidazolecarboxylic esters of the formulae IIIa, IIIb or mixturesthereof can be prepared by reacting carbonyldiimidazoles of the formulaeIa, Ib, Ic or mixtures thereof

where R¹ is C₁₋₄-alkyl and R² is hydrogen or methyl, with tert-butanolin a substituted aromatic hydrocarbon as solvent, and extracting theresulting reaction mixture with water to remove imidazoles of theformulae IIa and IIb

where R¹ und R² have the abovementioned meanings, which are also formed.

The carbonyldiimidazoles of the formulae Ia, Ib, Ic or mixtures thereofcan be obtained by reacting at least one imidazole of the formulae IIaand IIb with phosgene in a substituted aromatic hydrocarbon as solvent,wherein the hydrochloride, which is also formed, of the at least oneimidazole of the formulae IIa and IIb is removed from the reactionmixture by phase separation as melt.

The preparation of carbonyldiimidazole from imidazole and phosgene isgenerally disclosed in EP-A-0 692 476. However, the reaction (seeExample 1) results in imidazole hydrochloride as solid, which has to befiltered off. This requires a transfer of the reaction mixture, which isdisadvantageous because the carbonyldiimidazole which is formed is verymoisture-sensitive, and the workup is made difficult for this reason.

It has been found according to the invention that the hydrochlorides ofthe imidazoles of the formulae IIa and IIb result as liquids (melt)under the reaction conditions and can therefore be removed virtuallycompletely from the product mixture by a simple phase separation. Thehydrochlorides obtained in this way can be converted back byneutralization into the imidazoles of the formulae IIa and IIb andreturned to the synthesis.

Thus, compared with the process described in EP-A-0 692 476, the removalof the hydrochloride is considerably simplified, and the risk ofdecomposition of the required carbonyldiimidazoles is reduced.

The carbonyldiimidazoles of the formulae Ia, Ib and Ic are formed asmixture on reaction of imidazoles of the formulae IIa and/or IIb. Ashift of the double bonds and protons in the imidazoles is possibleduring the reaction, so that a product mixture is obtained even from asingle compound of the formulae IIa and IIb. However, the productpredominantly obtained is the one in which no shift of double bond andproton is necessary. The carbonyldiimidazoles of the formulae Ia, Ib, Icor mixtures thereof can be isolated by precipitation by cooling thereaction mixture. However, they can also be further processed directlyin the reaction mixture, after removal of the hydrochlorides of theimidazoles, without isolation being necessary. It is moreover possibleto employ the hot crude solution without further workup.

The carbonyldiimidazoles of the formulae Ia, Ib, Ic or mixtures thereofcan be employed for a large number of reactions, for example forpreparing corresponding tert-butyl imidazole-1-carboxylates, forcarbonyl group transfer, or for dehydration, especially for preparingesters and amides from carboxylic acids.

As a rule, phosgene is passed into the at least one imidazole of theformulae IIa and IIb in the solvent at from 60 to 130° C., preferably 80to 130° C., in particular 90 to 130° C. Solvents which can be used areall substituted aromatic hydrocarbons suitable for this purpose.Examples of preferably employed solvents are chlorobenzene, xylene ando-dichlorobenzene. Unreacted phosgene can be removed by stripping withinert gases such as nitrogen. The resulting reaction mixture can ifnecessary be heated further until a liquid two-phase system forms andphase separation becomes possible.

Conversion of the carbonyldiimidazoles of the formulae Ia, Ib, Ic ormixtures thereof into the imidazolecarboxylic esters of the formulaeIIIa and IIIb or mixtures thereof takes place by reaction withtert-butanol in a substituted aromatic hydrocarbon as solvent. Thispreferably entails employing a solvent as defined previously, which is,in particular, identical to the solvent used in the first reaction step.The reaction mixture obtained in the first reaction step can thus beused further without removing the solvent. The reaction withtert-butanol preferably takes place at from 50 to 140° C., particularlypreferably 60 to 120° C., in particular 70 to 90° C. The yield can inthis case be increased at a lower temperature. On reaction ofcarbonyldiimidazoles of the formulae Ia, Ib, Ic or mixtures thereof withtert-butanol there is formation not only of the required tert-butylesters but also of imidazoles of the formulae IIa and IIb. Theseimidazoles can be removed by extracting the resulting reaction mixturewith water. They can then be isolated from the aqueous imidazole phaseand be returned to the process for preparing the carbonyldiimidazoles.

It has been found according to the invention that the resulting reactionmixture can be extracted with water without decomposition (hydrolysis)of the imidazolecarboxylic esters of the formulae IIIa, IIIb or mixturesthereof. Simple extraction with water is therefore possible, with therequired imidazolecarboxylic esters being retained in the organic phase.After the solvent has been distilled off under reduced pressure, theycan be fractionally distilled in order to obtain the pureimidazolecarboxylic esters of the formulae IIIa, IIIb or mixturesthereof.

The invention also relates to a process for removing imidazoles fromreaction mixtures which contain imidazoles of the formulae IIa and IIbor mixtures thereof and imidazolecarboxylic esters of the formulae IIIaand IIIb or mixtures thereof by extracting the reaction mixture withwater.

The imidazolecarboxylic esters of the formulae IIIa, IIIb or mixturesthereof can also be prepared by reacting at least one imidazole of theformulae IIa and IIb with di-tert-butyl pyrocarbonate (BOC anhydride).The byproducts produced in this case are carbon dioxide andtert-butanol. However, the process described previously is preferredaccording to the invention because of the high costs of BOC anhydride.

In the compounds of the above formulae, R¹ is C₁₋₄-alkyl and R² ishydrogen or methyl. It is preferred for R¹ to be C₁₋₄-alkyl and R² to behydrogen. In this connection, R¹ can be methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, or tert-butyl. R¹ is preferably C₁₋₃-alkyl,in particular methyl or ethyl, specifically methyl.

The specifically preferred carbonyldiimidazoles of the formulae Ia, Ib,Ic are thus carbonyldi-4-methylimidazole,carbonyl-4-methylimidazole-5-methylimidazole andcarbonyldi-5-methylimidazole. The imidazoles of the formulae IIa and IIbemployed in these cases are 4-methylimidazole and 5-methylimidazole.4-Methylimidazole is particularly preferably employed in the synthesis.In this case, carbonyldi-4-methylimidazole is mainly obtained.

Reaction of the isomeric carbonyldimethylimidazoles with tert-butanolresults in tert-butyl 5- and 4-methylimidazole-1-carboxylates asimidazolecarboxylic esters of the formulae IIIa, IIIb. When4-methylimidazole is exclusively used originally it is mainly the4-methylimidazole isomer which is obtained. The content of the5-methylimidazole isomer is about 6 to 7%. The product mixture can bedistilled without decomposition at a boiling point of about 63-64° C.under 0.4 bar.

The imidazolecarboxylic esters of the formulae IIIa and IIIb or mixturesthereof can be used to introduce BOC protective groups into aminofunctionalities. A general process for this is described in Spec. Chem.13 (1993), 67-69. This entails compounds containing aminofunctionalities being reacted with imidazolecarboxylic esters of theformulae IIIa and IIIb or mixtures thereof. The imidazoles are liberatedagain during this, so that homogeneous protective groups are obtained,irrespective of the carboxylic ester isomer employed.

It is possible in the process according to the invention to prepare theimidazolecarboxylic esters of the formulae IIIa, IIIb and mixturesthereof, which are liquid at room temperature and can easily bedistilled, from chemicals which are easily obtainable at reasonable costin a one-pot process without workup of the intermediate.

The invention is explained in detail by means of examples hereinafter.

EXAMPLES Example 1 Preparation of carbonyldi-4-methylimidazole

2 mol of 4-methylimidazole were dissolved in chlorobenzene which hadbeen dehydrated by partial distillation. Then, at 60° C., 0.5 mol ofphosgene was passed in (until the phosgene refluxed). Reaction wasallowed to continue for 1 h after the introduction was complete, andthen the excess phosgene was stripped off with nitrogen. The suspensionwhich had formed was heated at 80 to 100° C. until the lower phase wascompletely molten. The lower phase was then completely removed. Itcontained exclusively methylimidazole hydrochloride.

The upper phase contained the carbonyldi-4-methylimidazole, whichcrystallized out incompletely on cooling. Carbonyldi-4-methylimidazolecan be either isolated by evaporating the solvent under reduced pressureor directly processed further in solution. Thecarbonyldi-4-methylimidazole always contains a proportion of isomericcarbonyl-4-methylimidazole-5-methylimidazole, which arises due tophosgene reacting with the other N atom. This is unimportant for furtheruse of the product because on use to protect the appropriate amino acidno imidazole residue remains in the target molecule.

Melting point of the carbonyldi-4-methylimidazole: 101-107° C.

Yield after isolation: 89%

IR: Carbonyl band at 1717 cm⁻¹ Calculated for C₉H₁₀N₄O: C, 56.83; H,5.30 N, 29.46. Found: C, 56.50; H, 5.30 N, 29.60.

Example 2 Preparation of tert-butyl 4-methylimidazole-1-carboxylate

2 mol of 4-methylimidazole were dissolved in xylene which had beendehydrated by partial distillation. Then, at 60° C., 0.5 mol of phosgenewas passed in (until the phosgene refluxed). Reaction was allowed tocontinue for 1 h after the introduction was complete, and then theexcess phosgene was stripped off with nitrogen. The suspension which hadformed was heated at 130° C. until the lower phase was completelymolten. The lower phase was completely removed.

The xylene solution of the carbonyldi-4-methylimidazole (upper phase)was mixed with an equimolar amount of tert-butanol and refluxed for 2hours. Conversion was checked by GC. (Formation of 4-methylimidazole andtert-butyl 4-methylimidazole-1-carboxylate, disappearance of thetert-butanol and carbonyldi-4-methylimidazole band).

After conversion was complete, the reaction solution was extracted twicewith water in order to remove the 4-methylimidazole from the solution.

The organic phase was fractionally distilled. The product(tert-butyloxycarbonyl-4-methylimidazole) distilled at 63-64° C. and 0.4mbar.

IR: Carbonyl band at 1752 cm⁻¹ Calculated for C₉H₁₄N₂O₂: C, 59.32; H,7.74; N, 15.37. Found: C, 59.10; H, 7.60; N 15.50.

The product contains a proportion of isomeric tert-butyl5-methylimidazole-1-carboxylate (6 to 7%). This is of no importance foruse as protective group reagent because there is exclusive transfer ofthe BOC group.

Example 3 Alternative Synthetic Route

47.96 g (0.22 mol) of di-tert-butyl pyrocarbonate (BOC anhydride) wereadded over the course of about 1 minute to a solution of 16.4 g (0.2mol) of 4-methylimidazole and 1.2 g (0.01 mol) of4-dimethylaminopyridine (DMAP) in 250 ml of dry acetonitrile under N₂and while stirring at 18° C. The reaction solution was warmed to 22° C.over the course of 5 minutes, and it was then stirred for 1 hour. Afterconcentration in a rotary evaporator at 45° C. under 10 to 20 mbar, 37.5g of liquid residue remained and were subjected to short-pathdistillation under 1 mbar.

At a bottom temperature of 82° C. and an overhead temperature of 65° C.,28.0 g of main distillate were obtained as clear, mobile liquid whichhad the following composition according to GC and NMR analyses:

83.0% tert-butyl 4-methylimidazole-1-carboxylate,

11.0% tert-butyl 5-methylimidazole-1-carboxylate

The initial distillate (6.5 g) contained a further 5.4 g of tert-butyl4-methylimidazole-1-carboxylate and 0.5 g of tert-butyl5-methylimidazole-1-carboxylate. (Distillation residue: 0.7 g).

The total yield of tert-butyl 4-methylimidazole-1-carboxylate was thus32.2 g (0.18 mol), 88%.

Example 4 Improved Process

1020 g of chlorobenzene were dehydrated by distilling off 20 g ofchlorobenzene. 164 g of 4-methylimidazole (2 mol) were added molten andwere dissolved. 50 g (0.5 mol) of phosgene were passed in over thecourse of 30 minutes at an internal temperature of 60-70° C. Subsequentreaction for one hour was followed by stripping with nitrogen; heatingwas continued during this until the solid lower phase was completelymolten (internal temperature 95° C.). The lower phase was then separatedoff at 95° C. (156 g).

74 g (1 mol) of tert-butanol were added dropwise over the course of 10minutes to the chlorobenzene phase at 82 to 76° C., and the reactionsolution was stirred at 80° C. for 5 h. The discharge was extractedtwice with 100 ml of water each time. The residue (85 g) after removalof the solvent by distillation under reduced pressure was fractionallydistilled. The main fraction distilled at 78-83° C. under 1.5 mbar. 66.2g of tert-butyl 4-methylimidazole-1-carboxylate were distilled,corresponding to a yield of 72.7%. The product contained about 4% of the5-methylimidazole isomer.

Example 5 Introduction of the BOC Protective Group on the Amino Group ofD,L-alanine

8.9 g of D,L-alanine (0.1 mol), 75 g of DMF and 30.4 g ofdiazabicycloundecene (“DBU”, 0.2 mol) are mixed. 23 g (0.12 mol) oftert-butyl 4-methylimidazole-1-carboxylate are added dropwise over thecourse of 10 minutes so that the temperature does not rise above 5° C.The mixture is then stirred at room temperature for 20 h. The dischargeis adjusted to pH 2.5 with 10% strength HCl at 0-5° C. It is extractedonce with methyl tert-butyl ether (MTBE). The organic phase isconcentrated under reduced pressure, whereupon the residue partiallycrystallizes. Suspension with cyclohexane results in colorless crystalsof melting point 105-106° C. The NMR spectrum and elemental analysisagree with reference data.

We claim:
 1. A process for preparing a carbonyidiimidazole of theformula Ia, Ib, Ic or a mixture thereof

where R¹ is C₁₋₄-alkyl and R² is hydrogen or methyl by the reaction ofat least one imidazole of the formula IIa or IIb

with phosgene in a substituted aromatic hydrocarbon as solvent, whereinthe hydrochloride, which is also formed, of said at least one imidazoleof the formula IIa or IIb is removed from the reaction mixture by phaseseparation as a melt.
 2. An imidazolecarboxylic ester of the formulaIIIa or IIIb or a mixture thereof

where R¹ is C₁₋₄-alkyl and R² is hydrogen or methyl.
 3. A process forpreparing an imidazolecarboxylic ester of the formula IIIa, IIIB or amixture thereof as claimed in claim 2 by reacting a carbonyidiimidazoleof the formula Ia, Ib, Ic or a mixture thereof

with tert-butanol in a substituted aromatic hydrocarbon as solvent andextracting the resulting reaction mixture with water to removeimidazoles, which are also formed, of the formulae IIa and IIb

where R¹ and R² have the above meanings.
 4. A process for preparing animidazolecarboxylic ester of the formula IIIa, IIIb or a mixture thereofas claimed in claim 2 by reacting at least one imidazole of the formulaIIa or IIb

wherein R¹ is C₁₋₄-alkyl and R² is hydrogen or methyl with di-tert-butylpyrocarbonate.